Compositions and methods for intravenous administration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone

ABSTRACT

The invention provides compositions and methods for intravenous administration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ), including formulations containing, autologous whole blood and ABDNAZ that can be rapidly administered to a patient by intravenous infusion without any significant pain at the site of infusion.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. Non-Provisional patentapplication Ser. No. 16/069,012, filed on Jul. 10, 2018, now U.S. Pat.No. 11,576,895, issued Feb. 14, 2023, which is the U.S. National Stageof PCT/US2017/012948, filed on Jan. 11, 2017, which claims the benefitof and priority to U.S. Provisional Patent Application Ser. 62/277,236,filed on Jan. 11, 2016, the contents of which are hereby incorporated byreference.

FIELD OF THE INVENTION

The invention provides compositions and methods for intravenousadministration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ),including formulations containing autologous whole blood and ABDNAZ thatcan be rapidly administered to a patient by intravenous infusion withoutany significant pain at the site of infusion.

BACKGROUND

Cancer is a significant health problem despite the many advances madefor detecting and treating this disease. Leading types of cancereliciting substantial numbers of patients include prostate cancer,breast cancer, and lung cancer. Prostate cancer is the most common formof cancer among males, with an estimated incidence of 30% in men overthe age of 50. Moreover, clinical evidence indicates that human prostatecancer has the propensity to metastasize to bone, and the diseaseappears to progress inevitably from androgen dependent to androgenrefractory status, leading to increased patient mortality. Breast cancerremains a leading cause of death in women. Its cumulative risk isrelatively high; certain reports indicate that approximately one ineight women are expected to develop some type of breast cancer by age 85in the United States Likewise, lung cancer is a leading cause ofcancer-related death, and non-small cell lung cancer (NSCLC) accountsfor about 80% of these cases.

Treatment options for cancer patients often include surgery,radiotherapy, chemotherapy, hormone therapy, or a combination thereof.The compound ABDNAZ described in, for example, U.S. Pat. Nos. 7,507,842;8,299,053; and 8,927,527 has been studied in multiple clinical trialsfor use in treating cancer. ABDNAZ is typically formulated as a mixturewith water, dimethylacetamide, and a poly(ethylene glycol) forintravenous infusion to the patient suffering from cancer. In clinicaltrials, patients receiving the aforementioned mixture of ABDNAZ byintravenous infusion have complained of significant pain at the site ofinfusion due to the ABDNAZ mixture. The significant pain at the site ofinfusion due to the ABDNAZ mixture has required medical personnel toreduce the rate at which the ABDNAZ mixture is administered to thepatient, sometimes requiring infusion times up to eight hours. The longinfusion times and slow rate of administration has, in some instances,limited the amount of ABDNAZ that can be administered to a patient whenthe ABDNAZ is used in combination with radiation therapy to be performedthe same day as administration of ABDNAZ.

The present invention provides a new formulation containing ABDNAZ thatcan be rapidly administered to the patient without causing anysignificant pain at the site of infusion and has other advantages asdescribed herein below.

SUMMARY

The invention provides compositions and methods for intravenousadministration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ),including formulations containing autologous whole blood and ABDNAZ thatcan be rapidly administered to a patient by intravenous infusion. Thecompositions and methods provide the further advantage that rapidadministration of the formulation does not result in any significantpain at the site of intravenous infusion due to the administration. Thecompound ABDNAZ has the following chemical structure:

The ABDNAZ formulations contain whole blood (preferably autologous wholeblood), ABDNAZ, and an anticoagulant. The formulations and methods areparticularly useful for administering ABDNAZ to a patient suffering fromcancer. The ABDNAZ formulations can be administered intravenously to thepatient at a rate of, for example, at least 5 mL/hour, 10 mL/hour, 30mL/hour, or higher rates. The rapid rate of administration reduces thetime required to administer a therapeutically effective amount of ABDNAZfor treating cancer, and has particular advantages when large doses ofADBDNAZ need to be administered to the patient during the same day asthe patient receives radiation therapy. The methods can be furthercharacterized according to the magnitude of pain experienced by thepatient at the site of administering the ABDNAZ formulation, wherein themagnitude of any pain experienced by the patient is small. The inventionhaving been generally described is explained in more detail in theaspects and embodiments below and in the detailed description.

One aspect of the invention provides a method for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer. The method comprises intravenouslyadministering to the patient in need thereof a therapeutically effectiveamount of an ABDNAZ formulation described herein (such as a formulationcomprising whole blood, ABDNAZ, and an anticoagulant) in order to treatthe cancer. The ABDNAZ formulation may be administered at a rate of, forexample, at least 5 mL/hour or at least 10 mL/hour. The method providesthe advantage of being able to rapidly administer ABDNAZ without causingundue pain at the site of administering the ABDNAZ formulation, and anysuch pain may be characterized according to, for example, the featurethat any such pain is no greater than Grade 1 pain.

Another aspect of the invention provides a method for rapid intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient, wherein the methodcomprises intravenously administering to the patient at a rate of, forexample, at least 10 mL/hour, an ABDNAZ formulation described herein(such as a formulation comprising whole blood, ABDNAZ, and ananticoagulant), wherein any pain experienced by the patient at the siteof intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 2. The ABDNAZ formulation may be further characterized accordingto the concentration of ABDNAZ in the formulation, such as where theformulation contains ABDNAZ at a concentration of, for example, at least10 μg/mL, at least 20 μg/mL, at least 50 μg/mL, at least 100 μg/mL, orat least 150 μg/mL.

Another aspect of the invention provides an intravenous formulationcontaining ABDNAZ for intravenous administration to a patient, whereinthe formulation comprises: (a) whole blood in an amount of at least 60%v/v of the formulation; (b) a polyethylene glycol at a concentration offrom about 0.4 μL/mL to about 30 μL/mL in the formulation; (c)N,N-dimethylacetamide at a concentration of from about 0.2 μL/mL toabout 15 μL/mL in the formulation; (d) ABDNAZ at a concentration of atleast 10 μg/mL in the formulation; (e) water; and (f) an anticoagulant.The intravenous formulations are suited for use in the methods describedherein, and provide the advantage of being able to be rapidlyadministered to the patient by intravenous infusion without causing anysignificant pain at the site of administration.

Another aspect of the invention provides a kit for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer. The kit comprises: (i) aformulation comprising ABDNAZ, and (ii) instructions for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer according to procedures describedherein. One benefit of the kit is that it provides an ABDNAZ formulationcapable of being rapidly administered to the patient by intravenousinfusion without causing any significant pain at the site ofadministration.

Another aspect of the invention provides a kit for id intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient. The kit comprises: (i) aformulation comprising ABDNAZ, and (ii) instructions for id intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient according to proceduresdescribed herein.

DETAILED DESCRIPTION

The invention provides compositions and methods for intravenousadministration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ),including formulations containing autologous whole blood and ABDNAZ thatcan be rapidly administered to a patient by intravenous infusion. Thecompositions and methods provide the further advantage that rapidadministration of the formulation does not result in any significantpain at the site of intravenous infusion due to the administration.

The ABDNAZ formulations contain whole blood (preferably autologous wholeblood), ABDNAZ, and an anticoagulant. The formulations and methods areparticularly useful for administering ABDNAZ to a patient suffering fromcancer. The ABDNAZ formulations can be administered intravenously to thepatient at a rate of, for example, at least 5 mL/hour, 10 ml/hour, 30mL/hour, or a higher rate. The rapid rate of administration reduces thetime required to administer a therapeutically effective amount of ABDNAZfor treating cancer, and has particular advantages when large doses ofADBDNAZ need to be administered to the patient during the same day asthe patient receives radiation therapy. The methods can be furthercharacterized according to the magnitude of pain experienced by thepatient at the site of administering the ABDNAZ formulation, wherein themagnitude of any pain experienced by the patient is small. Variousaspects of the invention are set forth below in sections; however,aspects of the invention described in one particular section are not tobe limited to any particular section.

I. Therapeutic Methods

The invention provides methods for intravenous administration of2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ). The methodsenable more rapid administration of ABDNAZ to a patient and avoid anysubstantial pain at the site of administration due to the ABDNAZ.Various features of the methods are described in sections below. Thesections are arranged for convenience and information in one section isnot limited to that section, but may be applied to other sections.

First Method

One aspect of the invention provides a method for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer. The method comprises intravenouslyadministering to the patient in need thereof a therapeutically effectiveamount of an ABDNAZ formulation comprising whole blood, ABDNAZ, and ananticoagulant, in order to treat the cancer. The whole blood ispreferably autologous whole blood.

The method may be further characterized according to the rate at whichthe ABDNAZ formulation is intravenously administered to the patient. Incertain embodiments, the ABDNAZ formulation is intravenouslyadministered to the patient at a rate of at least 3 mL/hour. In certainembodiments, the ABDNAZ formulation is intravenously administered to thepatient at a rate of at least 5 mL/hour. In certain embodiments, whereinthe ABDNAZ formulation is intravenously administered to the patient at arate of at least 10 mL/hour.

One benefit of the above method is that it substantially reduces theamount of pain experienced by the patient at the site of administeringABDNAZ. Accordingly, in certain embodiments, the method is characterizedby the feature that any pain experienced by the patient at the site ofintravenous administration of the ABDNAZ formulation due to intravenousadministration of the ABDNAZ formulation is no greater than Grade 2. Incertain other embodiments, any pain experienced by the patient at thesite of intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 1.

Second Method

Another aspect of the invention provides a method for intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient The method comprisesintravenously administering to the patient at a rate of at least 3mL/hour an ABDNAZ formulation comprising whole blood, ABDNAZ, and ananticoagulant, wherein any pain experienced by the patient at the siteof intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 2. In certain embodiments, the ABDNAZ formulation is intravenouslyadministered to the patient at a rate of at least 5 mL/hour

Third Method

Another aspect of the invention provides a method for rapid intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient. The method comprisesintravenously administering to the patient at a rate of at least 10mL/hour an ABDNAZ formulation comprising whole blood, ABDNAZ, and ananticoagulant, wherein any pain experienced by the patient at the siteof intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 2.

One benefit of the above method is that it substantially reduces theamount of pain experienced by the patient at the site of administeringABDNAZ. Accordingly, in certain embodiments, the method is characterizedby the feature that any pain experienced by the patient at the site ofintravenous administration of the ABDNAZ formulation due to intravenousadministration of the ABDNAZ formulation is no greater than Grade 1.

In certain embodiments, the patient is suffering from cancer.

Fourth Method

Another aspect of the invention provides a method for intravenousadministration of an ABDNAZ formulation to a patient while minimizinginjection site pain experienced by the patient The method comprisesintravenously administering to the patient at a rate of at least 3mL/hour an ABDNAZ formulation comprising ABDNAZ, an anticoagulant, and ablood product selected from the group consisting of an erythrocyte cell,blood plasma, and whole blood. The method may be further characterizedaccording to the feature that any pain experienced by the patient at thesite of intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 2. In certain embodiments, the ABDNAZ formulation is intravenouslyadministered to the patient at a rate of at least 5 mL/hour, or at least10 mL/hour. In certain embodiments, the blood product is an erythrocytecell. In certain embodiments, the ABDNAZ formulation comprises apopulation of erythrocyte cells, such as where the ABDNAZ formulationcomprises erythrocyte cells in an amount of at least about 2%, 5%, 8%,10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% by volume of the ABDNAZformulation.

Exemplary Features of the First, Second, Third, and Fourth Methods

The above methods may be further characterized by additional features,such as the rate of infusion of the ABDNAZ formulation, theconcentration of ABDNAZ in the ABDNAZ formulation, the identity ofcomponents in the ABDNAZ formulation, the amount of whole blood in theABDNAZ formulation, the volume of ABDNAZ formulation administered topatient, and other features as described in more detail below.

Rate of Infusion of ABDNAZ Formulation

The method may be further characterized according to the rate at whichthe ABDNAZ formulation is administered to the patient. Accordingly, incertain embodiments, the ABDNAZ formulation is intravenouslyadministered to the patient at a rate of at least 30 mL/hour. In certainembodiments, the ABDNAZ formulation is intravenously administered to thepatient at a rate of at least 60 mL/hour. In certain embodiments, theABDNAZ formulation is intravenously administered to the patient at arate of at least 90 mL/hour. In certain embodiments, the ABDNAZformulation is intravenously administered to the patient at a rate of atleast 120 mL/hour. In yet other embodiments, the ABDNAZ formulation isintravenously administered to the patient at a rate of at least 150mL/hour, 180 mL/hour, 210 mL/hour, 240 mL/hour, 270 mL/hour, 300mL/hour, 330 mL/hour, or 360 mL/hour. In yet other embodiments, theABDNAZ formulation is intravenously administered to the patient at arate in the range of from about 100 mL/hour to about 150 mL/hour, fromabout 150 mL/hour to about 200 mL/hour, from about 180 mL/hour to about220 mL/hour, from about 200 mL/hour to about 250 mL/hour, from about 250mL/hour to about 300 mL/hour, from about 275 mL/hour to about 325mL/hour, or from about 300 mL/hour to about 350 mL/hour.

Concentration of ABDNAZ in the ABDNAZ Formulation

The method may be further characterized according to the concentrationof ABDNAZ in the ABNDAZ formulation. Accordingly, in certainembodiments, the ABDNAZ formulation contains ABDNAZ at a concentrationof at least 10 μg/mL. In certain embodiments, the ABDNAZ formulationcontains ABDNAZ at a concentration of at least 20 μg/mL. In certainembodiments, the ABDNAZ formulation contains ABDNAZ at a concentrationof at least 50 μg/mL. In certain embodiments, the ABDNAZ formulationcontains ABDNAZ at a concentration of at least 100 μg/mL. In certainembodiments, the ABDNAZ formulation contains ABDNAZ at a concentrationof at least 150 μg/mL. In certain embodiments, the ABDNAZ formulationcontains ABDNAZ at a concentration in the range of about 10 μg/mL toabout 1 mg/mL. In certain embodiments, the ABDNAZ formulation containsABDNAZ at a concentration in the range of about 10 μg/mL to about 0.5mg/mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ ata concentration in the range of about 10 μg/mL to about 250 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 20 μg/mL, to about 200 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 200 ninth to about 750 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 200 μg/mL to about 400 about 400μg/mL to about 600 μg/mL, about 500 μg/mL to about 700 μg/mL, or about600 μg/mL to about 700 μg/mL.

Exemplary More Specific ABDNAZ Formulations

Exemplary more specific ABDNAZ formulations that may be used in themethods include, for example, formulations containing whole blood,ABDNAZ, an anticoagulant, and optionally one or more of water, apolyethylene glycol, and N,N-dimethylacetamide. In certain embodiments,the ABDNAZ formulation consists essentially of whole blood, ABDNAZ, andan anticoagulant. In certain embodiments, the ABDNAZ formulationconsists of whole blood, ABDNAZ, an anticoagulant, and optionally one ormore of water, a polyethylene glycol, and N,N-dimethylacetamide. Incertain embodiments, the ABDNAZ formulation consists of whole blood,ABDNAZ, an anticoagulant, and optionally one or more of water, apolyethylene glycol having a number-average molecular weight in therange of about 200 g/mol to about 600 g/mol, and N,N-dimethylacetamide.In certain embodiments, the ABDNAZ formulation consists of whole blood,ABDNAZ, an anticoagulant, water, a polyethylene glycol having anumber-average molecular weight in the range of about 200 g/mol to about600 g/mol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZformulation consists of whole blood, ABDNAZ, an anticoagulant, andoptionally one or more of water, a polyethylene glycol having anumber-average molecular weight of about 400 g/mol, andN,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulationconsists of whole blood, ABDNAZ, an anticoagulant, water, a polyethyleneglycol having a number-average molecular weight of about 400 g/mol, andN,N-dimethylacetamide.

Anticoagulant

The method may be further characterized according to the identity and/oramount of the anticoagulant. Accordingly, in certain embodiments, theanticoagulant comprises one or more of heparin and a citrate salt. Incertain embodiments, the anticoagulant is a solution comprising analkali metal citrate salt, dextrose, and water. In certain embodiments,the anticoagulant is present in the ABDNAZ formulation in an amountranging from about 0.1% wt/wt to about 15% w/w. In certain embodiments,the anticoagulant is present in the ABDNAZ formulation in an amountranging from about 1% wt/wt to about 10% w/w. In certain embodiments,the anticoagulant is present in the ABDNAZ formulation in an amountranging from about 2% wt/wt to about 8% w/w.

Amount of Whole Blood in the ABDNAZ Formulation

The method may be further characterized according to the amount of wholeblood in the ABDNAZ formulation. Accordingly, in certain embodiments,the whole blood constitutes at least 30% wt/wt of the ABDNAZformulation. In certain embodiments, the whole blood constitutes atleast 40% wt/wt of the ABDNAZ formulation. In certain embodiments, thewhole blood constitutes at least 50% wt/wt of the ABDNAZ formulation. Incertain embodiments, the whole blood constitutes at least 60% wt/wt ofthe ABDNAZ formulation. In certain embodiments, the whole bloodconstitutes at least 75% wt/wt of the ABDNAZ formulation. In certainembodiments, the whole blood constitutes at least 90% wt/wt of theABDNAZ formulation. In certain embodiments, the whole blood constitutesfrom about 60% wt/wt to about 99% wt/wt of the ABDNAZ formulation. Incertain embodiments, the whole blood constitutes from about 70% wt/wt toabout 95% wt/wt of the ABDNAZ formulation. In certain embodiments, thewhole blood constitutes from about 75% wt/wt to about 90% wt/wt of theABDNAZ formulation. In certain embodiments, there is from about 5 mL toabout 10 mL of whole blood in the ABDNAZ formulation, from about 10 mLto about 15 mL of whole blood in the ABDNAZ formulation, from about 9 mLto about 11 mL of whole blood in the ABDNAZ formulation, from about 10mL to about 20 mL of whole blood in the ABDNAZ formulation, from about20 mL to about 30 mL of whole blood in the ABDNAZ formulation, fromabout 30 to about 50 mL of whole blood in the ABDNAZ formulation, fromabout 50 mL to about 70 mL of whole blood in the ABDNAZ formulation, orfrom about 70 mL to about 90 mL of whole blood in the ABDNAZformulation. In certain embodiments, there is from about 90 mL to about110 mL of whole blood in the ABDNAZ formulation. In certain embodiments,there is from about 95 mL to about 105 mL of whole blood in the ABDNAZformulation. In certain embodiments, there is about 100 mL of wholeblood in the ABDNAZ formulation.

Volume of ABDNAZ Formulation Administered to Patient

The method may be further characterized according to the volume ofABDNAZ formulation administered to the patient. Accordingly, in certainembodiments, the ABDNAZ formulation has a volume in the range of about10 mL to about 200 mL. In certain embodiments, the ABDNAZ formulationhas a volume in the range of about 10 mL to about 15 mL, about 15 mL toabout 20 mL, about 20 mL to about 30 mL, or about 30 mL to about 50 mL.In certain embodiments, the ABDNAZ formulation has a volume in the rangeof about 50 mL to about 200 mL. In certain embodiments, the ABDNAZformulation has a volume in the range of about 75 to about 150 mL. Incertain embodiments, the ABDNAZ formulation has a volume in the range ofabout 90 mL to about 140 mL. In certain embodiments, the ABDNAZformulation has a volume in the range of about 100 mL to about 140 mL.In certain embodiments, the ABDNAZ formulation has a volume in the rangeof about 100 mL to about 120 mL.

Timeline for Administering ABDNAZ Formulation

The method may be further characterized according to the timeline foradministering the ABDNAZ formulation to the patient. Accordingly, incertain embodiments, intravenous administration of the ABDNAZformulation commences within about 1 hour after formation of the ABDNAZformulation. In certain embodiments, intravenous administration of theABDNAZ formulation commences within about 30 minutes after formation ofthe ABDNAZ formulation. In certain embodiments, intravenousadministration of the ABDNAZ formulation commences within about 20minutes after formation of the ABDNAZ formulation. In certainembodiments, intravenous administration of the ABDNAZ formulation iscomplete within about 6 hours after formation of the ABDNAZ formulation.In certain embodiments, intravenous administration of the ABDNAZformulation is complete within about 4 hours after formation of theABDNAZ formulation.

Obtaining Whole Blood for ABDNAZ Formulation

The method may optionally further comprise obtaining an aliquot of wholeblood from the patient, and then using said aliquot to prepare theABDNAZ formulation for administration to the patient.

Location of Intravenous Administration

The method may be farther characterized according to the location ofintravenous administration to the patient. In certain embodiments, theintravenous administration is central intravenous administration. Incertain embodiments, the intravenous administration is peripheralintravenous administration.

Dose of ABDNAZ Administered

Exemplary dosing amounts of ABDNAZ are provided according to the numberof milligrams of ABDNAZ to be administered to the patient based on thesurface area of the patient as measured in m². In certain embodiments,the dose ABDNAZ administered to the patient is from about 1 mg/m² toabout 2 mg/m², about 2 mg/m² to about 4 mg/m², about 4 mg/m² to about 6mg/m², about 6 mg/m² to about 8 mg/m², about 8 mg/m² to about 10 mg/m²,about 10 mg/m² to about 12 mg/m², about 12 mg/m² to about 14 mg/m²,about 14 mg/m² to about 16 mg/m², about 16 mg/m² to about 18 mg/m²,about 18 mg/m² to about 20 mg/m², about 20 mg/m² to about 25 mg/m²,about 25 mg/m² to about 30 mg/m², about 30 mg/m² to about 35 mg/m²,about 35 mg/m² to about 40 mg/m², about 40 mg/m² to about 45 mg/m²,about 45 mg/m² to about 50 mg/m², about 50 mg/m² to about 60 mg/m², orabout 60 mg/m² to about 75 mg/m².

The dose of ABDNAZ administered to the patient may be farthercharacterized according to both the amount of ABDNAZ and the mode ofdelivery, such as intravenous infusion Accordingly, in certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 1 mg/m² to about 90 mg/m². In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 1 mg/m² to about 10 mg/m². In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 1 mg/ml to about 2.5 mg/ml. In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 2.5 mg/ml to about 5 mg/ml. In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 5 mg/m² to about 10 mg/ml. In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 5 mg/m² to about 7 mg/m². In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 8 mg/ml to about 9 mg/ml. In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 10 mg/ml to about 20 mg/ml. In certainembodiments, each dose of the formulation comprising ABDNAZ isadministered to the patient by intravenous infusion providing ABDNAZ inan amount ranging from about 1 mg/ml to about 1.5 mg/ml, about 1.5 mg/mlto about 2 mg/ml, about 2 mg/ml to about 2.5 mg/ml, about 2.5 mg/ml toabout 3 mg/ml, about 3 mg/ml to about 3.5 mg/ml, about 3.5 mg/ml toabout 4 about 4 mg/ml to about 4.5 about 4.5 mg/ml to about 5 mg/ml,about 5 mg/ml to about 5.5 mg/ml, about 5.5 mg/ml to about 6 mg/ml,about 6 mg/ml to about 6.5 mg/ml, about 6.5 mg/ml to about 7 mg/ml,about 7 mg/ml to about 7.5 mg/ml, about 7.5 mg/ml to about 8 mg/ml,about 8 mg/ml to about 8.5 about 8.5 mg/ml to about 9 mg/ml, about 9mg/ml to about 9.5 mg/ml, about 9.5 mg/ml to about 10 mg/ml, about 10mg/ml to about 12 mg/ml, about 12 mg/ml to about 14 mg/ml, about 14mg/ml to about 16 mg/ml, about 16 mg/ml to about 18 mg/ml, about 18mg/ml to about 20 mg/ml, about 20 mg/ml to about 25 mg/ml, about 25mg/ml to about 30 mg/ml, about 30 mg/ml to about 35 mg/ml, about 35mg/ml to about 40 mg/ml, about 40 to about 45 mg/ml, or about 45 mg/mlto about 50 mg/ml. In certain embodiments, each dose of the formulationcomprising ABDNAZ is administered to the patient by intravenous infusionproviding ABDNAZ in an amount ranging from about 3 mg/ml to about 8mg/mL.

In more specific embodiments, each dose of the formulation comprisingABDNAZ is administered to the patient by intravenous infusion providingABDNAZ in an amount of about 1.25 mg/m², In certain embodiments, eachdose of the formulation comprising ABDNAZ is administered to the patientby intravenous infusion providing ABDNAZ in an amount of about 2.5mg/m², In certain embodiments, each dose of the formulation comprisingABDNAZ is administered to the patient by intravenous infusion providingABDNAZ in an amount of about 5 mg/m², In certain embodiments, each doseof the formulation comprising ABDNAZ is administered to the patient byintravenous infusion providing ABDNAZ in an amount of about 8.4 mg/m².In certain embodiments, each dose of the formulation comprising ABDNAZis administered to the patient by intravenous infusion providing ABDNAZin an amount of about 1 mg/m², about 1.5 mg/m², about 2 mg/m², about 2.5mg/m², about 3 mg/m², about 15 mg/m², about 4 mg/m², about 4.5 mg/m²,about 5 mg/m², about 5.5 mg/m², about 6 mg/m², about 6.5 mg/m², about 7mg/m², about 7.5 mg/m², about 8 mg/m², about 8.5 mg/m², about 9 mg/m²,about 9.5 mg/m², about 10 mg/m², about 12 mg/m², about 14 mg/m², about16 mg/m², about 18 mg/m², about 20 mg/m², about 25 trig/m², about 30mg/m², about 35 mg/m², about 40 mg/m² about 45 mg/m², or about 50 mg/m².

Extent of any Pain at Site of Intravenous Administration

The method may be further characterized according to the extent of anypain experienced by the patient at the site of intravenousadministration of the ABDNAZ formulation due to intravenousadministration of the ABDNAZ formulation. Accordingly, in certainembodiments, any pain experienced by the patient at the site ofintravenous administration of the ABDNAZ formulation due to intravenousadministration of the ABDNAZ formulation is no greater than Grade 2. Incertain other embodiments, any pain experienced by the patient at thesite of intravenous administration of the ABDNAZ formulation due tointravenous administration of the ABDNAZ formulation is no greater thanGrade 1. The Grade scale for evaluating pain is art-recognized andranges from 0 to 5, with zero being no pain and five being intense pain.General description of the pain Grades is provided in the table below

Grade of Pain General Description 0 No Pain 1 Barely noticeable pain 2Mild pain 3 Moderate pain 4 Very painful 5 Intense pain that is verydifficult to withstand for greater than 5 minutes

Type of Cancer

When the ABDNAZ formulation is being administered to a patient sufferingfrom cancer in order to treat the cancer, the method may be furthercharacterized according to type of cancer to be treated. For example, incertain embodiments, the cancer is a solid tumor. In certainembodiments, the cancer is brain cancer, bladder cancer, breast cancer,cervical cancer, cholangiocarcinoma, colon cancer, colorectal cancer,endometrial cancer, esophageal cancer, lung cancer, liver cancer,melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectalcancer, renal cancer, stomach cancer, testicular cancer, or uterinecancer. In certain embodiments, the cancer is brain cancer. In certainembodiments, the cancer is colorectal cancer. In certain embodiments,the cancer is cholangiocarcinoma or lung cancer.

In certain embodiments, the cancer is lung cancer. In certainembodiments, the lung cancer is small cell lung cancer. In certain otherembodiments, the cancer is non-small cell lung cancer. In certainembodiments, the cancer is a leukemia or lymphoma. In certainembodiments, the cancer is a B-cell lymphoma or non-Hodgkin lymphoma.

Additional exemplary cancers for treatment include, for example, bladdercancer, breast cancer, cervical cancer, colon cancer, colorectal cancer,endometrial cancer, esophageal cancer, leukemia, lung cancer, livercancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer,rectal cancer, renal cancer, stomach cancer, testicular cancer, anduterine cancer. In yet other embodiments, the cancer is a vascularizedtumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma,melanoma, glioma, neuroblastoma, sarcoma (e.g., an angiosarcoma orchondrosarcoma), larynx cancer, parotid cancer, bilary tract cancer,thyroid cancer, acral lentiginous melanoma, actinic keratoses, acutelymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma,adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, analcancer, anorectum cancer, astrocytic tumor, Bartholin gland carcinoma,basal cell carcinoma, biliary cancer, bone cancer, bone marrow cancer,bronchial cancer, bronchial gland carcinoma, carcinoid,cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma,chronic lymphocytic leukemia, chronic myeloid leukemia, clear cellcarcinoma, connective tissue cancer, cystadenoma, digestive systemcancer, duodenum cancer, endocrine system cancer, endodermal sinustumor, endometrial hyperplasia, endometrial stromal sarcoma,endometrioid adenocarcinoma, endothelial cell cancer, ependymal cancer,epithelial cell cancer, Ewing's sarcoma, eye and orbit cancer, femalegenital cancer, focal nodular hyperplasia, gallbladder cancer, gastricantrum cancer, gastric fundus cancer, gastrinoma, glioblastoma,glucagonoma, heart cancer, hemangiblastomas, hemangioendothelioma,hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatobary cancer,hepatocellular carcinoma, Hodgkin's disease, ileum cancer, insulinoma,intaepithelial neoplasia, interepithelial squamous cell neoplasia,intrahepatic bile duct cancer, invasive squamous cell carcinoma, ejunumcancer, joint cancer, Kaposi's sarcoma, pelvic cancer, large cellcarcinoma, large intestine cancer, leiomyosarcoma, lentigo malignamelanomas, lymphoma, male genital cancer, malignant melanoma, malignantmesothelial tumors, medulloblastoma, medulloepithelioma, meningealcancer, mesothelial cancer, metastatic carcinoma, mouth cancer,mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal tractcancer, nervous system cancer, neuroepithelial adenocarcinoma nodularmelanoma, non-epithelial skin cancer, non-Hodgkin's lymphoma, oat cellcarcinoma, oligodendroglial cancer, oral cavity cancer, osteosarcoma,papillary serous adenocarcinoma, penile cancer, pharynx cancer,pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma,rectal cancer, renal cell carcinoma, respiratory system cancer,retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, sinuscancer, skin cancer, small cell carcinoma, small intestine cancer,smooth muscle cancer, soft tissue cancer, somatostatin-secreting tumor,spine cancer, squamous cell carcinoma, striated muscle cancer,submesothelial cancer, superficial spreading melanoma, T cell leukemia,tongue cancer, undifferentiated carcinoma, ureter cancer, urethracancer, urinary bladder cancer, urinary system cancer, uterine cervixcancer, uterine corpus cancer, uveal melanoma, vaginal cancer, verrucouscarcinoma, VIPoma, vulva cancer, well differentiated carcinoma, or Wilmstumor.

Characterization of Anti-Cancer Effects

When the ABDNAZ formulation is being administered to a cancer patient inorder to treat the cancer, the therapeutic method may be furthercharacterized according to the anti-cancer effect of the treatment, suchas (i) a reduction in the size of at least one tumor in the patient,and/or (ii) reduction in the number of tumors in the patient.

Accordingly, in certain embodiments, the therapeutic method ischaracterized by at least a 20% reduction in the size of at least onetumor in the patient. In certain other embodiments, there is at least a35% reduction in the size of at least one tumor in the patient. Incertain other embodiments, there is at least a 50% reduction in the sizeof at least one tumor in the patient. In certain other embodiments,there is at least a 60%, 70%, 80% or 90% reduction in the size of atleast one tumor in the patient. In certain other embodiments, there isabout a 5%-50%, 10%-50%, 20%-50%, 5%-75%, 10%-75%, 20%-75%, or 50%-90%reduction in the size of at least one tumor in the patient.

When the cancer to be treated is a brain metastases, the method may befurther characterized according to the reduction in number and/or sizeof the brain metastases. In certain embodiments, there is at least a 20%reduction in the number of brain metastases in the patient. In certainother embodiments, there is at least a 35% reduction in the number ofbrain metastases in the patient. In yet other embodiments, there is atleast a 50% reduction in the number of brain metastases in the patient.In certain other embodiments, there is at least a 60%, 70%, 80% or 90%reduction in the number of brain metastases in the patient. In certainother embodiments, there is about a 5%-50%, 10%-50%, 20%-50%, 5%-75%,10%-75%, 20%-75%, or 50%-90% reduction in the number of brain metastasesin the patient.

Patients for Treatment

The therapeutic method may be further characterized according to thepatient to be treated. In certain embodiments, the patient is an adulthuman. In certain other embodiments, the patient is a pediatric human.

In certain embodiments, the patient does not suffer from anemia or havereduced blood volume. In certain embodiments, the patient has at least95% of the amount of their average daily blood volume.

Form of ABDNAZ

In certain embodiments, the patient may be administered apharmaceutically acceptable salt of ABDNAZ.

III. Exemplary More Specific ABDNAZ Formulations

One exemplary more specific formulation is an intravenous formulationcontaining ABDNAZ for intravenous administration to a patient,comprising:

-   -   a. whole blood in an amount of at least 60% v/v of the        formulation;    -   b. a polyethylene glycol at a concentration of from about 0.4        μL/mL to about 30 μL/mL in the formulation;    -   c. N,N-dimethylacetamide at a concentration of from about 0.2        μL/mL to about 15 μL/mL in the formulation;    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. water; and    -   f. an anticoagulant.

Another exemplary more specific formulation is a formulation thatconsists essentially of:

-   -   a. whole blood in an amount of at least 60% v/v of the        formulation;    -   b. a polyethylene glycol at a concentration of from about 0.4        μL/mL to about 30 μL/mL in the formulation;    -   c. N,N-di methylacetamide at a concentration of from about 0.2        μL/mL to about 15 μL/mL in the formulation;    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. water; and    -   f. an anticoagulant.

Another exemplary more specific formulation is a formulation thatconsists of:

-   -   a. whole blood in an amount of at least 60% v/v of the        formulation;    -   b. a polyethylene glycol at a concentration of from about 0.4        μL/mL to about 30 μL/mL in the formulation;    -   c. N,N-dimethylacetamide at a concentration of om about 0.2        μL/mL to about 15 μL/mL in the formulation;    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. water: and    -   f. an anticoagulant.

Another exemplary more specific formulation is an intravenousformulation containing ABDNAZ for intravenous administration to apatient, comprising:

-   -   a. a blood product (e.g., an erythrocyte cell, blood plasma, or        whole d) in an amount of at least 30% v/v of the formulation;    -   b. optionally a polyethylene glycol at a concentration of from        about 0.4 μL/mL to about 30 μL/mL in the formulation;    -   c. optionally N,N-dimethylacetamide at a concentration of from        about 0.2 μL/mL, to about 15 μL/mL in the formulation;    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. optionally water; and    -   f. optionally an anticoagulant.

Another exemplary more specific formulation is an intravenousformulation containing ABDNAZ for intravenous administration to apatient, comprising:

-   -   a. whole blood in an amount of at least 30% v/v of the        formulation;    -   b. a polyethylene glycol (e.g., at a concentration of from about        0.4 μL/mL to about 30 μL/mL in the formulation);    -   c. N,N-dimethylacetamide (e.g., at a concentration of from about        0.2 μL/mL to about 15 μL/mL in the formulation);    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. water; and    -   f. an anticoagulant.

Another exemplary more specific formulation is a formulation thatconsists essentially of:

-   -   a. whole blood in an amount of at least 30% v/v of the        formulation;    -   b. a polyethylene glycol (e.g., at a concentration of from about        0.4 μL/mL to about 30 μL/mL in the formulation);    -   c. N,N-dimethylacetamide (e.g., at a concentration of from about        0.2 μL/mL to about 15 μL/mL in the formulation);    -   d. ABDNAZ at a concentration of at least 10 μg/mL in the        formulation;    -   e. water; and    -   f. an anticoagulant.

Exemplary Features of Intravenous Formulation

The intravenous formulation may be characterized according to, forexample, the identity of a polyethylene glycol, anticoagulant,concentration of ABDNAZ, amount of whole blood and other featuresdescribed herein below.

Polyethylene Glycol

The formulation may be further characterized according to the identityof a polyethylene glycol in the ABDNAZ formulation. Accordingly, incertain embodiments, the polyethylene glycol is a polyethylene glycolhaving a number-average molecular weight in the range of about 200 g/molto about 600 g/mol. In certain embodiments, the polyethylene glycol is apolyethylene glycol having a number-average molecular weight of about400 g/mol.

In certain embodiments, the polyethylene glycol is present at aconcentration of from about 0.4 μL/mL to about 4 μL/mL in theformulation. In certain embodiments, the N,N-dimethylacetamide at aconcentration of from about 0.2 μL/mL to about 2 μL/mL in theformulation.

Anticoagulant

The formulation may be further characterized according to the identityof an anticoagulant in the ABDNAZ formulation. Accordingly, in certainembodiments, the anticoagulant comprises one or more of heparin and acitrate salt. In certain embodiments, the anticoagulant is a solutioncomprising an alkali metal citrate salt, dextrose, and water.

Concentration of ABDNAZ

The formulation may be further characterized according to theconcentration of ABDNAZ in the ABDNAZ formulation. Accordingly, incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration of at least 20 μg/mL. In certain embodiments, the ABDNAZformulation contains ABDNAZ at a concentration of at least 50 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration of at least 100 μg/mL. In certain embodiments, the ABDNAZformulation contains ABDNAZ at a concentration of at least 150 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 10 μg/mL to about 1 mg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 10 μg/mL to about 0.5 mg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 10 μg/mL to about 250 μg/mL. Incertain embodiments, the ABDNAZ formulation contains ABDNAZ at aconcentration in the range of about 20 μg/mL to about 200 μg/mL.

Amount of Whole Blood

The formulation may be further characterized according to the amount ofwhole blood in the ABDNAZ formulation. Accordingly, in certainembodiments, the whole blood constitutes at least 30% wt/wt of theformulation. In certain embodiments, the whole blood constitutes atleast 40% wt/wt of the formulation. In certain embodiments, the wholeblood constitutes at least 50% wt/wt of the formulation. In certainembodiments, the whole blood constitutes at least 75% wt/wt of theformulation. In certain embodiments, the whole blood constitutes atleast 90% wt/wt of the formulation. In certain embodiments, the wholeblood constitutes from about 60% wt/wt to about 99% wt/wt of theformulation. In certain embodiments, the whole blood constitutes fromabout 70% wt/wt to about 95% wt/wt of the formulation. In certainembodiments, the whole blood constitutes from about 75% wt/wt to about90% wt/wt of the formulation. In certain embodiments, there is fromabout 90 mL to about 110 mL of whole blood in the formulation. Incertain embodiments, wherein there is from about 95 mL to about 105 mLof whole blood in the formulation. In certain embodiments, there isabout 100 mL of whole blood in the formulation.

Unit Dose Form of Intravenous Formulation

The formulation may be further characterized according to the volume ofa unit dose of the ABDNAZ formulation. Accordingly, in certainembodiments, the formulation is in the form of a unit dose having avolume in the range of about 10 mL to about 200 mL. In certainembodiments, the formulation is in the form of a unit dose having avolume in the range of about 10 mL to about 15 mL, about 15 mL to about20 mL, about 20 mL to about 30 mL, about 30 mL to about 40 mL, or about40 mL to about 50 mL. In certain embodiments, the formulation is in theform of a unit dose having a volume in the range of about 50 mL to about200 mL. In certain embodiments, the formulation is in the form of a unitdose having a volume in the range of about 75 mL to about 150 mL. Incertain embodiments, the formulation is in the form of a unit dosehaving a volume in the range of about 90 mL to about 140 mL. In certainembodiments, the formulation is in the form of a unit dose having avolume in the range of about 100 mL to about 140 mL. In certainembodiments, the formulation is in the form of a unit dose having avolume in the range of about 100 mL to about 120 mL.

Characterization of Pain Effect Upon Intravenous Administration toPatient

The formulation may be further characterized according to the extent ofpain experienced by the patient upon intravenous administration of theABDNAZ formulation to the patient. Accordingly, in certain embodiments,the formulation is characterized by the feature that any painexperienced by the patient at the site of intravenous administration dueto intravenous administration of the formulation to the patient at arate in the range of 10 mL/hour to 50 mL/hour is no greater than Grade2. In certain embodiments, wherein the formulation is characterized bythe feature that any pain experienced by the patient at the site ofintravenous administration due to intravenous administration of theformulation to the patient at a rate in the range of 10 mL/hour to 50mL/hour is no greater than Grade 1.

The description above describes multiple aspects and embodiments of theinvention. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments.

IV. Kits for Use in Medical Applications

Another aspect of the invention provides a kit for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer. The kit comprises: (i) aformulation comprising ABDNAZ, and (ii) instructions for intravenousadministration of an ABDNAZ formulation to a patient suffering fromcancer in order to treat the cancer according to procedures describedherein.

Still another aspect of the invention provides a kit for rapidintravenous administration of an ABDNAZ formulation to a patient whileminimizing injection site pain experienced by the patient. The kitcomprises: (i) a formulation comprising ABDNAZ, and (ii) instructionsfor rapid intravenous administration of an ABDNAZ formulation to apatient while minimizing injection site pain experienced by the patientaccording to procedures described herein.

V. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms are preferablymammals (e.g., murines, simians, equines, bovines, porcines, canines,felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route.

As used herein, the term “treating” includes any effect, e.g.,lessening, reducing, modulating, ameliorating or eliminating, thatresults in the improvement of the condition, disease, disorder, and thelike, or ameliorating a symptom thereof.

As used herein, the terms “alleviate” and “alleviating” refer toreducing the severity of the condition, such as reducing the severityby, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 95%.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see, for example,Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co.,Easton, Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺ and NW₄ ⁺(wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The term “about” as used herein when referring to a measurable value(e.g., weight, time, and dose) is meant to encompass variations, such as±10%, ±5%, ±1%, or ±0.1% of the specified value.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention

Example 1—Intravenous Administration of an ABDNAZ Formulation Formed byCombining Whole Blood, ABDNAZ, and an Anticoagulant

As part of a clinical trial, twelve, adult human patients wereintravenously administered an ABDNAZ formulation formed by combiningwhole blood, ABDNAZ (4 mg), an anticoagulant, and certain othermaterials as described in more detail below. Intravenous administrationof the ABDNAZ formulation was performed at an initial flow rate of 5mL/minute. The procedure permitted an increase in the flow rate iftolerable to the patient. No patients reported experiencing pain at theinjection site. Further description of experimental procedures andresults are provided below.

Part I—Experimental Procedures

As part of a clinical trial, twelve, adult human patients wereintravenously administered an ABDNAZ formulation. The intravenousadministration was central venous administration. The ABDNAZ formulationwas prepared as follows

-   -   (1) Approximately 100 nit of the patient's blood as drawn and        then combined with an 11 mL aliquot of ACD-A solution (which is        an anticoagulant solution containing sodium citrate, such as        that commercially available from Citra Labs) to produce Solution        No. 1;    -   (2) Solution No. 1 was mixed with 4 of a solution containing        ABDNAZ (4 mg), polyethylene glycol having a number average        molecular weight of 400 g/mol (6% w/w), dimethylacetamide (3%        w/w), and water for injection, to produce the ABDNAZ        formulation.

The ABDNAZ formulation was passed through a sterile filter andintravenously administered to the patient at an initial flow rate of 5mL/minute. The flow rate could be increased if tolerable to the patient.At an infusion rate of 5 mL/minute, the ABDNAZ formulation having avolume of 115 mL can be intravenously administered in about 23 minutes.

Part II—Results

No patients reported experiencing pain at the injection site.

Example 2—Intravenous Administration of an ABDNAZ Formulation ContainingABDNAZ, PEG-400, Dimethylacetamide, and Water

An aqueous solution of ABDNAZ was intravenously administered totwenty-five human patients as part of a Phase I clinical study. Theaqueous solution contained ABDNAZ (2 mg/mL), polyethylene glycol havinga number average molecular weight of 400 g/mol (6% w/w),dimethylacetamide (3% w/w), and water for injection. Patients wereadministered a volume of the aqueous solution of ABDNAZ sufficient todeliver a dose of ABDNAZ in the amount of 10 mg/m², 16.7 mg/m², 24.6mg/m², 33 mg/m², 55 mg/m², or 83 mg/m². Pain at the injection site dueto administration of the aqueous solution of ABDNAZ was experienced by84% of patients. The first patient to receive the aqueous solution ofABDNAZ by central intravenous administration over a period of 20 minutesto deliver a 10 mg/m² dose of ABDNAZ experienced infusion-site pain andnasopharyngeal burning sensation of such high intensity that the patientvoluntarily withdrew from the study. Thereafter, peripheral intravenousdelivery in the antecubital or forearm area was used and a longerduration of time was used to perform the infusion (e.g., ranging from 2hours to 8 hours, while administering at a rate of 3.5 mL/hour thatcould be adjusted up or down in 0.5 mL/hour increments based onpatients' ability to tolerate the infusion). Further description ofexperimental procedures and results are provided below.

Part I—Experimental Procedures

In this open-label, human, dose-escalation phase 1 study, a 3+3dose-escalation design was used to assess safety, tolerability, andpharmacokinetics of ABDNAZ. Patients were enrolled from the Universityof California-San Diego Moores Cancer Center, La Jolla, Calif., USA, andthe Sarah Cannon Research Institute, Nashville, Tenn., USA. Eligiblepatients were 18 years or older with histologically confirmed advancedsolid tumours for which standard curative treatment did not exist. Allpatients had an Eastern Cooperative Group performance status of 2 orless, an estimated life expectancy of at least 12 weeks, and adequatelaboratory parameters (absolute neutrophil count ≥1.5×10⁶ cells per L,platelet count ≥7.5×10⁶ cells per L, haemoglobin ≥90 g/L, serum totalbilirubin ≤427.5 union, aspartate aminotransferase and alanineaminotransferase concentration times the upper normal limit [ULN; <5times the ULN for hepatic, involvement], and creatinine clearance >50 mLper min). Previous antineoplastic therapies had to have beendiscontinued at least 6 weeks before intervention start, and patientscould show no residual side-effects of previous therapies. Patients wererequired to practice effective contraception while receiving ABDNAZ. Allpatients had evaluable disease. Key exclusion criteria includedhypoalbuminaemia (albumin <30 g/L), active brain metastases (althoughpatients with stable brain metastases were eligible), pregnancy orbreast feeding, any other clinically significant illness or psychiatricdisorder that could affect compliance or endpoint assessments, andconcurrent use of any other investigational drugs.

Screening assessments were done at the clinical site less than 16 daysbefore treatment initiation and included an electrocardiogram,urinalysis, Modified Borg Dyspnea Assessment, pulse oximetry, andradiographic tumour measurement. A medical history, physicalexamination, pregnancy test, performance status, complete blood count, acomprehensive serum chemistry, and urinalysis were done within 16 daysof the first dosing.

The protocol was reviewed and approved by the investigational reviewboards at the Moores Cancer Center and the Sarah Cannon ResearchInstitute. All procedures were performed in accordance with theprinciples established by the Helsinki Declaration. Patients gavewritten informed consent for all clinical and research aspects of thestudy before enrolment, which was done according to national andinstitutional guidelines.

An aqueous solution of ABDNAZ was intravenously administered topatients. The aqueous solution contained ABDNAZ (2 mg/mL), polyethyleneglycol having a number average molecular weight of 400 g/mol (6% w/w),dimethylacetamide (3% w/w), and water for injection. Patients wereadministered a volume of the aqueous solution of ABDNAZ sufficient todeliver a dose of ABDNAZ in the amount of 10 mg/m², 16.7 mg/m², 24.6mg/m², 33 mg/m², 55 mg/m², or 83 mg/m². Three patients were given astarting dose of 10 mg/m² of ABDNAZ before dose escalation (to 16.7mg/m², 24.6 mg/m², 33 mg/m², 55 mg/m and 83 mg/m²), with at least threepatients per dose cohort, allowing a 2-week observation period beforedose escalation. The duration of infusion was titrated to patienttolerance and varied between dose cohorts and patients However, for thefirst patient in the 10 mg/m² dose cohort, the aqueous solution ofABDNAZ was administered centrally over 20 min, and the patientexperienced infusion-site pain and nasopharyngeal burning sensation ofsuch high intensity that the patient voluntarily withdrew from thestudy. Thereafter, peripheral intravenous delivery in the antecubital orforearm area was used and a longer duration of time was used to performthe infusion (e.g., ranging from 2 hours to 8 hours, while administeringat a rate of 3.5 mL/hour that could be adjusted up or down in 0.5mL/hour increments based on patients' ability to tolerate the infusion).The peripheral intravenous delivery was better tolerated; most patientsshowed a prominent dose-dependent vasodilation in the forearm andtransient mild-to-moderate pain. For some patients in the highest dosecohort (83 mg/m we had to split the total dose and delivery of ABDNAZinto a twice-weekly regimen Three patients in the highest dose cohortand one patient in the penultimate dose cohort (55 mg/m² needed a dosereduction to 33 mg/m² because of localized infusion pain.

Part II—Results

Pain at the injection site, mostly grade 1 and grade 2, was the mostcommon adverse event related to treatment, experienced by 21 (84%)patients. Other common ABDNAZ-related adverse events included armswelling or oedema (eight [32%] patients), and vein hardening (seven[28%] patients). Time constraints related to management of infusion painfrom ABDNAZ resulted in a maximally feasible dose of 83 mg/m²,ABDNAZ-related adverse events observed during the study are listed inthe table below.

10 mg/m² 16.7 mg/m² 24.6 mg/m² 33 mg/m² 55 mg/m² 83 mg/m² Dose Dose DoseDose Dose Dose ABDNAZ ABDNAZ ABDNAZ ABDNAZ ABDNAZ ABDNAZ (n = 6) (n = 3)(n = 3) (n = 4) (n = 3) (n = 6) Adverse Grade Grade Grade Grade GradeGrade Grade Grade Grade Grade Grade Grade Event 1-2 3 1-2 3 1-2 3 2 31-2 3 1-2 3 Infusion- 4 0 3 0 1 0 3 1 3 0 6 0 site pain (67%) (100%)(33%) (75%) (25%) (100%) (100%) Arm 0 0 1 0 0 0 1 0 2 0 4 0 swelling or(33%) (25%) (67%) (67%) oedema Vein 0 0 0 0 0 0 1 0 1 0 5 0 hardening(25%) (33%) (83%) Dyspnoea 1 0 0 0 0 0 0 0 1 0 3 0 or (17%) (33%) (50%)wheezing Mouth 0 0 0 0 0 0 0 0 2 0 2 0 tingling or (67%) (33%) burning

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1.-77. (canceled)
 78. An intravenous formulation containing ABDNAZ for intravenous administration to a patient, comprising: a. whole blood in an amount of at least 60% v/v of the formulation; b. a polyethylene glycol at a concentration of from about 0.4 μL/mL to about 30 μL/mL, in the formulation; c. N,N-dimethylacetamide at a concentration of from about 0.2 μL/mL to about 15 μL/mL in the formulation; d. ABDNAZ at a concentration of at least 10 μL/mL in the formulation; e. water; and f. an anticoagulant.
 79. The intravenous formulation of claim 78, wherein the formulation consists essentially of: a. whole blood in an amount of at least 60% v/v of the formulation; b. a polyethylene glycol at a concentration of from about 0.4 μL/mL to about 30 μL/mL in the formulation; c. N,N-dimethylacetamide at a concentration of from about 0.2 μL/mL to about 15 μL/mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg/mL in the formulation; e. water; and f. an anticoagulant.
 80. The intravenous formulation of claim 78, wherein the formulation consists of: a. whole blood in an amount of at least 60% v/v of the formulation; b. a polyethylene glycol at a concentration of from about 0.4 μL/mL to about 30 μL/mL in the formulation; c. N,N-dimethylacetamide at a concentration of from about 0.2 μL/mL to about 15 μL/mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg/mL in the formulation; e. water; and f. an anticoagulant.
 81. The intravenous formulation of claim 78, wherein the polyethylene glycol is a polyethylene glycol having a number average molecular weight in the range of about 200 g/mol to about 600 g/mol.
 82. The intravenous formulation of claim 78, wherein the polyethylene glycol is a polyethylene glycol having a number average molecular weight of about 400 g/mol.
 83. The intravenous formulation of claim 78, wherein the anticoagulant comprises one or more of heparin and a citrate salt.
 84. The intravenous formulation of claim 78, wherein the anticoagulant is a solution comprising an alkali metal citrate salt, dextrose, and water.
 85. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration of at least 20 μg/mL.
 86. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration of at least 50 μg/mL.
 87. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration of at least 100 μg/mL.
 88. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration of at least 150 μg/mL.
 89. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration in the range of about 10 μg/mL to about 1 mg/mL.
 90. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration in the range of about 10 μg/mL to about 0.5 mg/mL.
 91. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration in the range of about 10 μg/mL to about 250 μg/mL.
 92. The intravenous formulation of claim 78, wherein the ABDNAZ formulation contains ABDNAZ at a concentration in the range of about 20 μg/mL to about 200 μg/mL.
 93. The intravenous formulation of claim 78, wherein the whole blood constitutes at least 60% wt./wt. of the formulation.
 94. The intravenous formulation of claim 78, wherein the whole blood constitutes at least 75% wt./wt. of the formulation.
 95. The intravenous formulation of claim 78, wherein the whole blood constitutes at least 90% wt./wt. of the formulation.
 96. The intravenous formulation of claim 78, wherein the whole blood constitutes from about 60% wt./wt. to about 99% wt./wt. of the formulation.
 97. The intravenous formulation of claim 78, wherein the whole blood constitutes from about 70% wt./wt. to about 95% wt./wt. of the formulation.
 98. The intravenous formulation of claim 78, wherein the whole blood constitutes from about 75% wt./wt. to about 90% wt./wt. of the formulation.
 99. The intravenous formulation of claim 78, wherein there is from about 90 mL to about 110 mL of whole blood in the formulation.
 100. The intravenous formulation of claim 78, wherein there is from about 95 mL to about 105 mL of whole blood in the formulation.
 101. The intravenous formulation of claim 78, wherein there is about 100 mL of whole blood in the formulation.
 102. The intravenous formulation of claim 78, wherein there is about 10 mL to about 20 mL of whole blood in the formulation.
 103. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 50 mL to about 200 mL.
 104. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 75 mL to about 150 mL.
 105. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 90 mL to about 140 mL.
 106. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 100 mL to about 140 mL.
 107. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 100 mL to about 120 mL.
 108. The intravenous formulation of claim 78, wherein the formulation is in the form of a unit dose having a volume in the range of about 10 mL to about 30 mL.
 109. The intravenous formulation of claim 78, wherein the polyethylene glycol is present at a concentration of from about 0.4 μL/mL to about 4 μL/mL in the formulation.
 110. The intravenous formulation of claim 78, wherein the N,N-dimethylacetamide at a concentration of from about 0.2 μL/mL to about 2 μL/mL in the formulation.
 111. The intravenous formulation of claim 78, wherein the formulation is characterized by the feature that any pain experienced by the patient at the site of intravenous administration due to intravenous administration of the formulation to the patient at a rate in the range of 10 mL/hour to 50 mL/hour is no greater than Grade
 2. 112. The intravenous formulation of claim 78, wherein the formulation is characterized by the feature that any pain experienced by the patient at the site of intravenous administration due to intravenous administration of the formulation to the patient at a rate in the range of 10 mL/hour to 50 mL/hour is no greater than Grade
 1. 